Process for forming chewable quickly dispersing comestible unit and product therefrom

ABSTRACT

The present invention deals with compositions and methods for preparing comestible units which disperse quickly in the mouth, especially when chewed. The present invention also includes the product made therefrom. The method includes initiating crystallization of shearform matrix with crystallization/bindig promoter and combining it with an additive to form flowable, compactible micro-particulates. The combination is then shaped to form a comestible unit having high structural integrity, good appearance, and excellent release characteristics.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.08/259,258, filed Jun. 14, 1994, which was a continuation-in-partapplication of U.S. application Ser. No. 08/133,669 filed Oct. 7, 1993,now U.S. Pat. No. 5,597,416 and a continuation-in-part of U.S.application Ser. No. 08/119,974 filed Sep. 10, 1993, now U.S. Pat. No.5,518,551. Reference is also made to commonly-owned U.S. Pat. Nos.5,622,719, and 5,587,172. The contents of all of these are incorporatedherein.

BACKGROUND OF THE INVENTION

The present invention relates to the art of making chewable comestibledosage units, such as tablets, which disintegrate quickly in the mouth.

Dosage units in the form of tablets are usually prepared by compressinga formulation containing a medicinal substance or drug and otheringredients, such as excipients selected for properties which facilitateproduction and use of the tablet. There are currently three known basicmethods for preparing tablet granulations. These are wet granulation,dry granulation and direct compression. Both wet and dry granulationsinvolve the formation of an agglomerate for feeding to a die cavity.Direct compression usually involves compressing a powder blend of anactive ingredient with suitable excipients.

Wet granulation is an expensive process because it requires manyprocessing steps and involves considerable material handling equipment.Consequently, the process requires both energy and substantial spacewhich should be environmentally controlled.

Generally, free water and heat are inimical to active ingredient. Wetgranulation procedures involve water and/or heat. Therefore, it isdesirable to provide a method for making tablets in the substantialabsence of heat and free water in order to enhance the survival ofactive ingredients incorporated in the tablet.

Dry granulation refers to the granulation of a powder mixture bycompression without the use of heat and solvent. Dry granulation is usedwhen wet granulation is not available because the drug is sensitive tomoisture or heat.

Dry granulation has many disadvantages. It requires a specializedheavy-duty tablet press to form the slug; it does not permit uniformcolor distribution as can be achieved with wet granulation, where dyecan be incorporated into the binder liquid; the pressure roll presscannot be used with insoluble drugs because this may retard thedissolution rate; and the process tends to create dust therebyincreasing the potential for cross-contamination.

Direct compression tabletting has the least amount of steps. Directcompression is used in a process by which tablets are compresseddirectly from powder blends of the active ingredient and suitableexcipients (including fillers, disintegrants, and lubricants).

Direct compression also has many technological limitations. Theselimitations include primarily obtaining sufficient flow, and obtainingbonding of particles to form a strong compressed tablet. Low-dose drugsare difficult to blend, that is, uniform distribution of the drug is noteasily attained and unblending sometimes occurs during the compressionstage. High-dose drugs do not lend themselves to direct compressionbecause of poor flowability and poor compressibility. A typical examplewould be some of the antacid drugs, such as aluminum hydroxide andmagnesium carbonate.

A disadvantage of all prior art processes is the production of finesusually associated with making compression tablets. In the prior art,preparation of particles for formulation of tablets by compressionresults in a noticeable amount of fines, i.e., very tiny particles onthe order of 150 microns and less. These fines can interfere withoperation of apparatus for feeding tabletting machines as well as theoperation of the tabletting machines. This adds to the cost ofproduction of the tablets.

Technology has been developed by the common owner of the presentapplication and U.S. Pat. No. 5,654,003. The patent discloses a uniqueprocedure in which compression tabletting can be simply and accuratelymanufactured by "fuse and compression" steps. Fusion is achieved byflash flow processing the tablet ingredients to provide shearform matrixmasses which are subsequently compressed to form comestible compressionunits. This process includes advantages of wet and dry granulation anddirect compression but does not have the disadvantages associated withthese prior art procedures.

In commonly-owned patent U.S. Pat. No. 5,622,719, a rapidly-dissolvingunit dosage and preparation and apparatus for making same are disclosed.The method disclosed therein includes mixing uncured shearform matrixmaterial with an additive followed by lightly compressing the resultingmixture to form a dosage unit. The formed unit is subsequently cured byexposing to controlled ambient heat, moisture, and pressure.

Applicants' assignee also has several patents which relate to otherunique delivery means. U.S. Pat. No. 4,855,326 discloses a fiber form ofmedicament-bearing product which can be compacted to form a sheet-likebody. However, the compact body cannot be squeezed too much for fear ofbreaking the fibrous mass.

In U.S. Pat. No. 4,997,856, a wafer-like structure is disclosed in whicha medicament is distributed on or through spun fibers which are thenchopped by passing through a conventional "food grinder" (Hobarthamburger grinder). The enclosed volume of the end product is less than30%, and preferably less than 15% of the as-spun volume of floss.

The use of compacted spun fibers is also disclosed in U.S. Pat. Nos.5,034,421 and 5,096,492.

While the procedure described in U.S. Pat. No. 5,622,719 discloses atechnique for making a rapidly dissolving dosage unit, none of the otherprocedures provide a technique for forming a dosage unit which quicklydisintegrates in the mouth of the consumer, but which can beconveniently manufactured for shipment and sales.

SUMMARY OF THE INVENTION

The present invention deals with compositions and methods for preparingcomestible units which quickly disperse in the mouth of the consumer,especially when chewed, and the units themselves. The method includesinitiating crystallization of shearform matrix before combining theshearform matrix with an additive to form flowable, compactiblemicro-particulates. The combination, which includes at least partiallycrystallized shearform matrix, is then compacted to form the comestibleunit.

In most preferred forms of the invention, the active ingredient is anantacid and the crystallization/binding promoter is ethanol.

It has also been found that when calcium is included as an activeingredient, the release characteristics of the dosage unit are veryfavorable. As a matter of fact, the unit can actually be used as acalcium supplement because of its high calcium release characteristics.

One manifestation of the present invention is a method of administeringan active ingredient to a human host. The method includes ingesting aquick dissolve comestible unit prepared by the method of the presentinvention. The next step requires the host to retain the quick dissolveunit in the oral cavity for a time sufficient to contact the unit withsaliva while in the oral cavity. Finally, the human host can introducewater to the oral cavity, while the unit is retained therein, to enhancedissolution of the dosage unit.

Other embodiments of the invention involve chewable comestible units.These units, which are preferably tablets, are specially formulated andprocessed so that they are easily chewable and readily soluble whenchewed. Water can be used to enhance dispersion/dissolution afteringestion.

Moreover, the dispersability of the unit is perceived as nearlyinstantaneous when chewed. Consequently, the consumer does not sense theeffects of unpleasant ingredients lingering in the oral cavity.

Tablets containing antacids, e.g., calcium carbonate, can be made whichhave no chalky taste or mouthfeel. In addition, they can be madechewable, while retaining the friability of tablets.

It is, therefore, an object of the invention to provide another methodfor preparing a chewable dosage unit which quickly disintegrates in themouth.

These and other advantages and objects of the present invention will beappreciated from the following description. The description and theexamples are not intended to limit the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention have been chosen for purposes ofillustration and description, but are not intended in any way torestrict the scope of the present invention. The preferred embodimentsof certain aspects of the invention are shown in the accompanyingdrawings, wherein:

FIG. 1 is a schematic representation of the ingredients before formingflowable, compactible micro-particulates;

FIG. 2 is a schematic representation of micro-particulates formed fromthe mixture shown in FIG. 1; and

FIG. 3 is a schematic representation of compacting micro-particulatesinto a comestible unit in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a method of making chewable comestible unitswhich disintegrate quickly in the mouth of the consumer and the unitsmade therewith. The units produced in accordance with the presentinvention are soft and easily chewed. They disintegrate nearlyinstantaneously, i.e., within seconds, in the mouth. However, theseunits, which can be tablets, are capable of being manufactured so thatthey can be handled for packaging and distribution without deteriorationof the integrity of the comestible units.

The first step of the method is to mix shearform matrix and an additive,such as an active ingredient. "Shearform matrix" in the presentinvention means a matrix or floss produced by subjecting a feedstockwhich contains a carrier material to flash flow processing.

Flash flow processing can be accomplished several ways. Flash-heat andflash-shear are two processes which can be used. In the flash-heatprocess the feedstock material is heated sufficiently to create aninternal flow condition which permits part of the feedstock to move atsubparticle level with respect to the rest of the mass and exit openingsprovided in the perimeter of a spinning head. The centrifugal forcecreated in the spinning head flings the flowing feedstock materialoutwardly from the head so that it reforms with a changed structure. Theforce necessary to separate and discharge flowable feedstock iscentrifugal force produced by the spinning head.

"Flash heat" describes a process in which a feedstock is subjected totemperature, thermogradients, flow, flow rates and other forces of thetype produced in certain types of machines

One preferred apparatus for implementing a flash heat process is a"cotton candy" fabricating type of machine. Another is set forth in U.S.Ser. No. 964,257, filed Sep. 30, 1992.

Any other apparatus or physical process which provides similar forcesand temperature gradient conditions can also be used. Useful devices arediscussed in the U.S. Ser. No. 08/854,344, filed May 12, 1997,incorporated herein by reference.

In the flash-shear process, a shearform matrix is formed by raising thetemperature in the feedstock material which includes a non-solubilizedcarrier, such as a saccharide-based material, until the carrierundergoes internal flow upon application of a fluid shear force. Thefeedstock is advanced and ejected while in internal flow condition, andsubjected to disruptive fluid shear force to form multiple parts ormasses which have a morphology different from that of the originalfeedstock.

The multiple masses are cooled substantially immediately after contactwith the fluid shear force and are permitted to continue in a free-flowcondition until solidified.

The flash shear process can be carried out in an apparatus which hasmeans for increasing the temperature of a non-solubilized feedstock andmeans for simultaneously advancing it for ejection. A multiple heatingzone twin screw extruder can be used for increasing the temperature ofthe non-solubilized feedstock. A second element of the apparatus is anejector which provides the feedstock in a condition for shearing. Theejector is in fluid communication with the means for increasing thetemperature and is arranged at a point to receive the feedstock while itis in internal flow condition. The ejector is preferably a nozzle whichprovides high pressure ejection of the feedstock material. See U.S. Pat.No. 5,380,473, which is incorporated herein by reference.

The feedstock for producing shearform matrix includes a carriermaterial. The carrier material can be selected from materials which arecapable of undergoing both physical and/or chemical changes associatedwith flash-flow processing. Materials useful as matrices may be chosenfrom those carbohydrates which are capable of forming free-formagglomerates upon being processed.

Preferred carrier materials are chosen from such classes as sugars orsugar derivatives. "Sugars" are those substances which are based onsimple crystalline mono- and di-saccharide structures, i.e., based on C₅and C₆ sugar structures. "Sugars" include simple sugars, e.g., glucose,sucrose, maltose, lactose, arabinose, xylose, ribose, fructose, mannose,pentose, galactose sorbose, dextrose, and sugar alcohols, e.g.,sorbitol, xylitol, mannitol, pentatol, maltitol, isomalt, sucralose andmixtures of any of these.

Preferred combinations of sugars include the sugars above used incombination with other mono-, di-, tri-, and polysaccharides in amountsup to 50% of the total amount, preferably up to 30%, and most preferablyup to 20%.

A shearform product is used in the technique of the present invention toobtain the new sugar product. A shearform sugar product is asubstantially amorphous sugar which results from subjecting sugar toheat and shear sufficient to transform crystalline (usually granulated)sugar to amorphous sugar without the use of a solution. Thus, in thesense of the present invention, a shearform sugar product ischaracterized as a sugar product resulting from a non-solubilized sugar.It is the starting material for forming the unique crystalline productof the present invention.

Other carrier materials can be used, but preferably in combination withsugar--not as a total replacement.

Maltodextrins are an example of other carrier materials. Maltodextrinsinclude those mixtures of carbohydrates resulting from hydrolysis of asaccharide feedstock which are described as solids having a DE of up toand including 65.

The feedstock can also include maltooligosaccharides produced byselective hydrolysis of cornstarch followed by removal of high and lowmolecular weight compounds. The general description ofmaltooligosaccharides as contemplated herein is set forth in U.S. Pat.No. 5,387,431.

Polydextrose is also contemplated for use in combination with sugar inthe carrier. Polydextrose is a non-sucrose, essentially non-nutritivecarbohydrate substitute. It can be prepared through polymerization ofglucose in the presence of polycarboxylic acid catalyst and polyols.Generally, polydextrose is known to be commercially available in threeforms: polydextrose A and polydextrose K, which are powdered solids, andpolydextrose N supplied as a 70% solution. Each of these products alsocontain some low molecular weight components, such as glucose, sorbitoland certain oligomers. Regarding polydextrose, Applicants incorporateherein the contents of U.S. Pat. No. 5,279,849.

Polydextrose may be used as both a carrier and a crystallization/bindingpromoter.

"Initiating crystallization" in the present invention means to inducecrystallization. Shearform matrix used in the present invention containsa substantial amount of amorphous sugar. Crystallization can beinitiated several ways. For example, crystallization promoters can beincluded in the feedstock used to make the shearform matrix.Crystallization promoters include surface active agents such as Tweens™,Spans™, and polydextrose, and mixtures thereof. Crystallization can alsobe initiated by adding a crystallization agent to the matrix before orafter combining with an additive. Therefore, initiating crystallizationin the present invention can occur before or after combining with theadditive.

"Combining" an additive with shearform matrix to form flowable,compactible micro-particulates means to add and mix an additive beforeor after initiating crystallization to form a medium which consists ofmicro-particulates. Micro-particulates are discreet entities whichappear to "roll" readily or "flow" in response to force of gravityand/or agitation. On a macroscopic scale micro-particulates appear as aflowable mass or medium. Consequently, the medium can be easily used intabletting machinery without clogging and/or creation of undue dust inthe ambient atmosphere.

The shearform matrix of the present invention is retrieved fromprocessing, and generally "chopped" before combining with the additives.The additives can be any ingredient or ingredients, preferably activeingredients, needed to supply the comestible unit with requiredcharacteristics. Preferably, the primary additives include one or moremedicinal substances.

Medicinal substances and other active ingredients which can be used inthe present invention are varied. A non-limiting list of such substancesis as follows: mineral supplements, vitamins, antacids, analgesics,anti-inflammatory substances, gastrointestinal agents, and mixturesthereof.

Especially preferred active ingredients are antacids. Antacid productscan be prepared using calcium carbonate alone or in combination withmagnesium hydroxide, and/or aluminum hydroxide and other antacidmaterials listed below.

Another group of preferred actives uses combinations of calciumcarbonate and/or another antacid with one or more H₂ -antagonists asanti-ulcerative agents. Useful H₂ -antagonists include: cimetidine,famatidine, omeprazole, and ranitidine and mixtures.

Vitamins such as Vitamin D can also be included in antacid-containingdosages.

It is contemplated that active agent(s) and optionalcrystallization/binding promoter(s) are ingredients in the formulationsfrom which the matrices are made.

The invention also includes a composition for delivering an activeingredient wherein the active ingredient is incorporated in a moldedsaccharide-based crystalline structure, which may have abi-dimensionally stabilized crystalline sugar. The sugar is produced byforming a sugar crystalline frame from an outer portion of an amorphousshearform sugar mass, and subsequently converting the remaining portionof the mass to a substantially completely crystalline structure. Theproduct is preferably monodispersed and is also preferablymicrocrystalline. For definitions of "monodispersed" and"microcrystalline," as well as definitions relating to other aspects ofthe present invention, reference is made to U.S. Pat. No. 5,597,416,which is incorporated herein by reference. The shearform mass can alsoinclude an additive which is co-crystallized in a crystalline product.The amorphous shearform mass is substantially rod-shaped, and has twodimensions lying in a cross-sectional plane of the rod. The singledimension extends along a linear axis of the rod. Preferably, themonodispersed structurally stabilized cross-section does not exceed 50μm, and preferably does not exceed 10 μm.

Other ingredients which may be included are fragrances, dyes, sweetenersboth artificial and natural, and other additives.

For example, fillers may be used to increase the bulk of the tablet.Some of the commonly used fillers are calcium sulfate, both di- andtribasic, starch, calcium carbonate, microcrystalline cellulose,modified starches, lactose, sucrose, mannitol, and sorbitol.

Other materials which can be incorporated into the feedstock to enhancethe shearform matrix include flavors and sweeteners (other than thecarrier itself).

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationthereof. A non-limiting representative list of examples includes citrusoils such as lemon, orange, grape, lime and grapefruit and fruitessences including apple, pear, peach, grape, strawberry, raspberry,cherry, plum, pineapple, apricot or other fruit flavors.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral, i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime) decanal (orange, lemon), aldehydeC-8 (citrus fruits), aldehyde C-9 (citrus fruits), adlehyde C-12 (citrusfruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (greenfruit), and 2-dodecenal (citrus, mandarin), mixtures thereof and thelike.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and mixturesthereof (when not used as a carrier); saccharin and its various saltssuch as the sodium salt; dipeptide sweeteners such as aspartame;dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside);chloro derivatives of sucrose such as sucralose; sugar alcohols such assorbitol, mannitol, xylitol, and the like. Also contemplated arehydrogenated starch hydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof. Other sweeteners may also be used.

Yet a further embodiment of the present invention includes the use of aneffervescent disintegration agent. Its action can aid in the masking ofobjectionable taste of active ingredients such as antacids, vitamins,and/or minerals, etc. It is generally believed that the positiveorganoleptic sensation achieved by the effervescent action in the mouth,as well as the texture, speed and sensation of disintegration agentsassist in masking undesirable flavor notes in the mouth.

In preferred embodiments of the present invention, the effervescentdisintegration agent may include at least one acid selected from thegroup consisting of citric acid, tartaric acid, malic acid, fumaricacid, adipic acid, succinic acid, acid anhydrides and acid salts andmixtures thereof, and at least one base selected from the groupconsisting of carbonate salts, bicarbonate salts and mixtures thereof.

Also as previously mentioned, the ingredients of the effervescent agentcan be included in one of at least three different ways. The firstmethod includes incorporating the entire effervescent agent in thefeedstock which is used to form the shearform product. The second mannerof incorporating an effervescent disintegrating agent is to include theentire agent as an additive which is mixed with shearform matrix afterit is formed. The third method contemplates incorporating one portion ofthe disintegrating agent in the shearform matrix and another portion ofthe disintegrating agent as an additive after formation of the shearformmatrix material. The artisan will determine the best way to preserve theagent for its disintegrative and effervescent properties upon ingestionby the host.

The shearform matrix used in the inventive process must be uncuredbefore it is molded. "Uncured" means amorphous or having a degree ofamorphousness which enables the formation of a dosage unit upon curing."Curing" means transforming the matrix from amorphous to crystallinewhile being sufficiently bound to produce a stable structure.

Curing can be enhanced by crystallization modifiers. Crystallizationmodifiers can be added to the feedstock before flash flow processing,such modifiers include, but are not limited to, surfactants (Spans™ andTweens™), dextrose, polyethylene glycol (PEG), polypropylene glycol(PPG), etc. These modifiers generally provide controlled acceleration ofcrystallization while the matrix is bound.

Crystallization modifiers enhance the formation of a crystalline frameand the conversion of the remaining mass. "Enhancement" as used hereinprincipally means acceleration of the process. "Enhancement" alsoincludes contribution to the strength of the crystalline structure, andpredictability of results. Other benefits, such as reduced-size product,can be achieved by use of crystallization modifiers.

Crystallization modifiers, which are preferably added to sugars beforethey are processed to amorphous shearform mass (or are optionally coatedon the sugar), are used to affect the rate of crystallization. Wateritself is a crystallization modifier, and is preferably included in theamorphous shearform sugar mass in an amount of between about 0.5% toabout 2.0%. Materials found to be most effective as crystallizationmodifiers are surfactants having a hydrophilic to lipid balance (HLB) ofsix or greater, i.e., they have the same degree of hydrophilicity assurfactants characterized by degree of HLB. Such materials include, butare not limited to anionic, cationic and zwitterionic surfactants aswell as neutral materials which have an HLB of six or greater. Preferredmodifiers are hydrophilic materials having polyethylene oxide linkages.Also, preferred materials have a molecular weight of at least 200 andpreferably at least 400.

Lecithin is one surface active agent for use in the present invention.Lecithin can be included in the feedstock in an amount of from about0.25 to about 2.00% by weight. Other surface active agents include, butare not limited to, the Spans™ and Tweens™ which are commerciallyavailable from ICI Americas Inc. Carbowax™ is yet anothercrystallization modifier which is very useful in the present invention.Preferably, Tweens™ or combinations of surface active agents are used toachieve the desired HLB.

One or more fillers may be used to increase the bulk of the tablet. Someof the commonly used fillers are calcium sulfate, both di- and tribasic, starch, calcium carbonate, microcrystalline cellulose, modifiedstarches, lactose, sucrose, mannitol, and sorbitol.

Other ingredients include one or more binders which contribute to theease of formation and general quality of the tablet. Binders includestarches, pregelatinize starches, gelatin, polyvinylpyrrolidone,methylcellulose, sodium carboxymethylcellulose, ethylcellulose,polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.

Lubricants are also useful in tabletting formulations. Lubricants caninclude, but are not limited to, one or more of the following: magnesiumstearate, calcium stearate, zinc stearate, hydrogenated vegetable oils,sterotex, polyoxyethylene, monostearate, talc, polyethyleneglycol,sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate andlight mineral oil.

Furthermore, one or more dispersion enhancers can be used to enhance thebreakability of the compressed tablet in an aqueous environment. Thedispersants can include starch, alginic acid, polyvinylpyrrolidones,guar gum, kaolin, bentonite, purified wood cellulose, sodium starchglycolate, isoamorphous silicate, and microcrystalline cellulose as highHLB emulsifier surfactants. In view of the ease with which the productof the present invention disintegrates, there is little need fordisintegrants.

The combination of shearform matrix and the additive must be provided asflavorable, compactible micro-particulates. The micro-particulatesinclude the ingredients of the mixture, but are relatively low density.The micro-particulates can then be compacted under relatively highcompaction force to form a low density dosage unit having highstructural integrity, strength and excellent appearance.

Micro-particulates are preferably formed by combining the mixture withat least one crystallization/binding promoter such as ethanol(preferably 200 proof), polyvinylpyrrolidone, or a combination thereof,as well as other agents which enhance the formation ofmicro-particulates, e.g., surface active agents, without increasing thedensity of the mixture. Ethanol is used in amounts of about 2.0 to about5.0%, preferably about 4.0%, based on the total weight of the flossformulation. After ethanol contact, the floss is treated to removeexcess ethanol and optionally milled or screened.

In some cases, a low compression force is used. Tablets made using theinvention can have low densities and can be easily disintegrated.

"Compacting" in the present invention means to shape into a comestibleunit, e.g., a tablet, at a pressure which need not be as great as normaltabletting pressure.

As a result of the present invention, a quickly dispersable comestibleunit can be manufactured for shipment and sales to consumers. Suchmanufacturing can proceed on a continuous basis. Since the agglomeratecan be compacted with low to moderate compaction forces, a unit can beformed which is durable and can withstand the handling associated withpackaging and distribution.

When chewable tablets are made, they are compressed to hardnesses ofabout 3 to about 15 SCU's, preferably about 4 to 6 SCU's. Thicknesses ofabout 0.25 to about 0.3 inches are typical.

Other ingredients can also be used in the present invention eitherduring the mixing stage, during the agglomeration stage, or after theagglomeration stage. Such ingredients include glidants which adhere tothe cohesive materials and enhance flow properties. Glidants which canbe used include one or more of: starch, talc, magnesium and calciumstearate, zinc stearate, dibasic calcium phosphate, magnesium carbonate,magnesium oxide, calcium silicate, silica arogels, and the like.

Also color additives can be used in preparing tablets. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

The present invention is particularly useful for preparing antacidtablets. Antacids are conveniently provided in a chewable tablet form toprovide a convenient method of delivering antacid to the consumer. Thechewable form provides an advantage in that the tablet is broken up intogranules during chewing and mixed with saliva before swallowing. Thiscreates a suspension.

One of the disadvantages of current antacid tablets is that the mass ofingredients residing in the mouth during and after chewing haveobjectionable texture and taste. The present invention overcomes thesedisadvantages because of the rapid disintegration which occurs in themouth. The objectionable texture and taste of disagreeable ingredientsare reduced because the residence time in the mouth is substantiallyreduced.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, calcium carbonate,calcium phosphate, citrate ion (acid or salt), amino acetic acid,hydrate magnesium aluminate sulfate, magaldrate, magnesiumaluminosilicate, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, magnesium oxide, magnesium trisilicate, milksolids, aluminum mono-ordibasic calcium phosphate, tricalcium phosphate,potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesiumaluminosilicates, tartaric acids and salts. Mixtures can be used.

Referring to FIGS. 1-3, the process of the present invention isdescribed in greater detail. In FIG. 1, a combination of shearformmatrix in the form of chopped floss material is depicted in mixture witha representative of an additive, i.e., +'s. An antacid agent is apreferred additive, +. In FIG. 1, the combination is shown as floss andadditive particles indiscriminately mixed one with another. There is nofixed relationship between the particles in the mixture. Crystallizationof the floss is initiated either before or after the combination with anadditive is formed.

In FIG. 2, the combination is shown as flowable, compactiblemicro-particulates. The micro-particulates shown in FIG. 2 arerepresented by collections of shearform matrix with the additive fixedtherein and thereon. The transformation is enhanced when the combinationshown in FIG. 1 is subjected to a crystallization/binding promoter suchas ethanol, polyvinylpyrrolidone, or a combination thereof. Othercrystallization/binding promoters may be used to form themicro-particulates.

The micro-particulates form a medium which is flowable. Therefore, themedium is easily fed to dye cavities in tabletting apparatus withoutclogging moveable parts, and the incidence of dust is reduced.

FIG. 3 is a schematic representation of the performance of themicro-particulates during actual compression. The micro-particulates areschematically represented under compaction force. They deform, but theirdensity is not increased. Basically, the spaces betweenmicro-particulates are reduced or virtually eliminated by agglomeration,but the micro-particulates themselves retain their low density. Additiveparticles are retained in and on the surface of the agglomerates.

Micro-particulates retain their individual integrity and lines ofdisintegration throughout the resulting unit. Moreover, since the masscan be subjected to relatively high-pressure-compaction (or compression)the surface of the resulting dosage unit is smooth, and the strength ofthe tablet is relatively high. The resulting units can be easily handledwithout deterioration of the surface appearance or destruction of thecomestible units.

During formation of the micro-particulates the material preferablycontains up to 5% water, and most preferably up to 1% water. The watercan be provided by water contained in the ingredients such as thatcarried in the sugars or binders. Water can also be provided in smallamounts in the alcohol, such as in 200 proof alcohol which absorbsmoisture rapidly and generally contains small amounts of moisture, e.g.,up to 1% by weight. Moisture can also be provided by ambientsurroundings such as the humidity in the air.

EXAMPLES Antacid Example

Shearform matrixes were prepared for use in the process of the presentinvention. The matrixes were prepared by subjecting combinations ofcarrier material to flash flow processing in a cotton candy typeapparatus. The combination included the saccharide-based carriermaterial sucrose, as well as other carriers, and surfactants such asTween™ 80, which is supplied by ICI, and lecithin. The isomalt usedherein is commonly available as Palatinit™ brand isomalt. The blendswere provided according to the formulae set forth below in the ShearformMatrix Table.

                  TABLE    ______________________________________    SHEARFORM MATRIX            AMOUNT (PERCENT) IN EACH MATRIX (M)    Ingredient              M1     M2     M3   M4   M5   M6   M7    ______________________________________    Sucrose   66.5   66.5   66.5 66.5 66.5 --   --    (granules)    Mannitol  33.0   16.5   28.0 31.0 24.0 --   --    (powered)    Dextrose  --     16.5    5.0 --   --   --   20.0    Sorbitol  --     --     --    2.0 --   --   --    Surfactant               0.5    0.5    0.5  0.5  0.5  1.4  1.4    Isomalt   --     --     --   --   --   95.6 20.0    Maltitol  --     --     --   --   --   --   55.6    Polyglycerol              --     --     --   --   --    3.0  3.0    esters    ______________________________________

The matrix recovered from each of the blends set forth above was a lightcolored floss, e.g., substantially white. Each matrix was then choppedfor mixing with an additive, e.g., an antacid combination. The examplesset forth hereinbelow refer to the matrices recovered from each of theblends above as M1, M2, . . . etc.

Antacid Example I

The first antacid example was mixed in accordance with the formula setforth below in Antacid Table I.

                  TABLE I    ______________________________________    ANTACID    Ingredient                 Percentage    ______________________________________    Antacid Agent (CaCO.sub.3) 36.55%    M1                         58.63%    Flavoring                  0.35%    Vegetable Oil              0.50%    Flow Agent    Syloid 244                     1.00%    Cab-O-Sil 0.40%    Starch                     2.00%    High Intensity Sweetener (Aspartame)                               0.07%    Lubricant (Mg Stearate)    0.50%                               100.00%    ______________________________________

The ingredients were combined by mixing to provide a mixture such asthat shown in FIG. 1.

After the mixture was formed, ethanol (200 proof) was added and flowablecompactible micro-particulates were formed. (About 4.0% of ethanol basedon the weight of the mixture was used). The schematic representation ofsuch agglomerates are shown in FIG. 2. After an agglomerate consistencywas achieved, tablets were formed by compressing under a compositionforce of about 6 SCU. The weight of each tablet was about 1.500 grams.

The tablets so formed had an excellent appearance, and disintegratedimmediately in the mouth of the consumer. The release capabilities ofthe calcium from the dosage unit has been set forth below in the CalciumRelease Table. As can be seen from the release capabilities, not only isthe dosage unit an excellent source of antacid agent, but can also beclassified as a source of calcium for purposes of nutrition. Therefore,the dosage unit can be characterized as a nutritional calciumsupplement.

Antacid Example II

A second example was prepared using the mixture set forth below inAntacid Table II.

                  TABLE II    ______________________________________    ANTACID    Ingredient              Percentage    ______________________________________    Antacid Agent (CaCO.sub.3)                            35.55%    M2                      58.86%    Peppermint Flavoring    0.12%    (Peppermint Oil)    Vegetable Oil           0.50%    Flow Agent    Syloid 244                  1.00%    Cab-O-Sil  0.40%    Starch                  2.00%    High Intensity Sweetener                            0.07%    (Aspartame)    Lubricant (Mg Stearate) 0.50%                            100.00%    ______________________________________

The above ingredients were mixed together and then subjected toagglomerating in the presence of ethanol (200 proof). About 4% ofethanol based on the weight of the mixture was used. Flowable,compactible micro-particulate were formed.

The resulting agglomerate was directed to tabletting press andcompressed at a compression force of about 6 SCU. The resulting tabletswere smooth and had a high quality appearance. Furthermore, the productdisintegrated immediately in the mouth of the consumer. Tests were alsoconducted on two of the samples to determine the release characteristicsof the calcium. The results of the test are shown in the Release Tableas tests results IIa and IIb.

Antacid Example III

Another example of an antacid dosage unit was prepared in accordancewith the mixture set forth in Antacid Table III.

                  TABLE III    ______________________________________    ANTACID    Ingredient                 Percentage    ______________________________________    Antacid Agent (CaCO.sub.3) 36.550%    M2                         58.630%    Flavoring                  0.350%    Vegetable Oil              0.500%    Flow Agent    Syloid 244                     1.000%    Cab-O-Sil 0.400%    Starch                     2.000%    High Intensity Sweetener (Aspartame)                               0.0700%    Lubricant (Mg Stearate)    0.500%                               100.000%    ______________________________________

The ingredients set forth above were thoroughly mixed and flowable,compactible micro-particulates were formed. The agglomerates were formedin the presence of ethanol added in an amount sufficient to form themicro-particulate consistency (about 4% by weight of the total mixture).The ethanol was mixed thoroughly with the ingredients and theagglomeration formed.

The micro-particulate medium was then directed to a tablet forming presswherein tablets were prepared using a compaction pressure of about 6SCU. The resulting tablets were at a high quality appearance, and wereable to disintegrate immediately in the oral cavity.

Furthermore, the tablets prepared in accordance with this example weresubjected to analysis for calcium release and the results have been setforth in the Calcium Release Table hereinbelow.

Antacid Example IV

Another antacid example was prepared in accordance with the formulationset forth in Antacid Table IV.

                  TABLE IV    ______________________________________    ANTACID    Ingredient                 Percentage    ______________________________________    Antacid Agent (CaCO.sub.3) 36.55%    M2                         58.59%    Flavoring                  0.35%    Vegetable Oil              0.05%    Flow Agent    Syloid 244                     1.00%    Cab-O-Sil 0.40%    Starch                     2.00%    High Intensity Sweetener (Aspartame)                               0.07%    Lubricant (Mg Stearate)    0.50%    Red Coloring (FD&C No. 40) 0.04%                               100.00%    ______________________________________

The ingredients set forth above were thoroughly mixed until thehomogenous red color appeared throughout the mixture. The mixture wasthen combined in the presence of ethanol (200 proof) in order to enhanceformation of flowable, compactible micro-particulates. Themicro-particulate medium was consistent in red color. The resultingagglomerates were tabletted using a compaction pressure of about 6 SCU.

The tablets formed therefrom had a good quality appearance including aconsistent red color and a smooth surface. Furthermore, the tablets soprepared disintegrated immediately in the mouth of the consumer. Thetablets prepared in accordance with the formulation set forth above weresubjected to calcium release testing and the results have been set forthbelow in the Calcium Release Table.

Antacid Example V

Another antacid dosage unit was prepared in accordance with theformulation set forth below in Antacid Table V.

                  TABLE V    ______________________________________    ANTACID    Ingredient              Percentage    ______________________________________    Antacid Agent (CaCO.sub.3)                            36.55%    M1                      58.83%    Peppermint Flavoring    0.15%    (Peppermint Oil)    Vegetable Oil           0.50%    Flow Agent    Syloid 244                  1.00%    Cab-O-Sil  0.40%    Starch                  2.00%    High Intensity Sweetener                            0.70%    (Aspartame)    Lubricant (Mg Stearate) 0.50%                            100.00%    ______________________________________

The ingredients were blended thoroughly and then subjected toagglomeration by addition of ethanol while mixing. The ethanol was addedin an amount of about 4% by weight of the mixture.

The resulting flowable, compactible micro-particulate medium was thensubjected to tabletting by compression in a tabletting unit at acompaction pressure of about 6 SCU. Each tablet weighed 1.500 grams.

The resulting tablets had a high quality appearance and disintegratedimmediately in the oral cavity. Furthermore, the tablets were subjectedto three separate tests to determine the calcium releasecharacteristics. The results have been set forth in the Calcium ReleaseTable as Va, Vb and Vc.

Antacid Example VI

A sixth antacid example was prepared using the formulation set forthbelow in Antacid Table VI.

                  TABLE VI    ______________________________________    ANTACID    Ingredient                 Percentage    ______________________________________    Antacid Agent (CaCO.sub.3) 36.55%    M3                         58.83%    Mint Flavor (Mint Blend)   0.15%    Vegetable Oil              0.50%    Flow Agent    Syloid 244                     1.00%    Cab-O-Sil 0.40%    Starch                     2.00%    High Intensity Sweetener (Aspartame)                               0.07%    Lubricant (Mg Stearate)    0.50%                               100.00%    ______________________________________

The ingredients set forth above were mixed until a homogeneous mixturewas achieved. Flowable compactible micro-particulates were then formedby addition of ethanol (200 proof) and blended until themicro-particulate were formed. The micro-particulate agglomerates werethen used to form tablets under compaction pressure of about 6 SCU.

The resulting tablets has an excellent taste and good appearance andwere easily disintegrated in the mouth of the consumer. Calcium releasetests were performed on the tablets and the results have been reportedin the Calcium Release Table set forth below.

Antacid Example VII

A seventh antacid dosage unit was prepared in accordance with theformulation set forth in Antacid Table VII.

                  TABLE VII    ______________________________________    ANTACID    Ingredient                 Percentage    ______________________________________    Antacid Agent (CaCO.sub.3) 36.55%    M4                         58.73%    Flavor                     0.25%    Vegetable Oil              0.50%    Flow Agent    Syloid 244                     1.00%    Cab-O-Sil 0.40%    Starch                     2.00%    High Intensity Sweetener (Aspartame)                               0.07%    Lubricant (Mg Stearate)    0.50%                               100.00%    ______________________________________

The ingredients were blended and agglomerated to form flowable,compactible micro-particulates by use of 200 proof ethanol. Theresulting micro-particulate medium was subjected to tabletting and thetablet press had a compaction pressure of about 6 SCU.

The resulting tablets had a smooth surface, excellent appearance andstructural integrity. Moreover, the tablets disintegrated immediately inthe mouth of the consumer. The calcium release characteristics were alsoexcellent and have been reported herein in the Calcium Release Table.

Antacid Example VIII

Another antacid example was prepared using the formulation set forthbelow in Antacid Table VIII.

                  TABLE VIII    ______________________________________    ANTACID    Ingredient                 Percentage    ______________________________________    Antacid Agent    CaCO.sub.3                     29.50%    Mg (OH).sub.2               5.79%    M1                             59.99%    Flavoring                      0.35%    Vegetable Oil                  0.50%    Flow Agent    Syloid 244 1.00%    Starch                     2.00%    High Intensity Sweetener (Aspartame)                               0.07%    Lubricant (Mg Stearate)    0.50%    Crystallization/Binding Promoter                               0.30%    (Polyvinylpyrrolidone)                               100.00%    ______________________________________

The above ingredients were combined and then subjected to agglomerationby adding ethanol (200 proof) and mixing until a flowable, compactiblemicro-particulate medium was formed. It is noted thatpolyvinylpyrrolidone and ethanol were combined in the present mixture asa crystallization/binding promoter. Polyvinylpyrrolidone is included asan ingredient in Antacid Table VIII. Ethanol was added after the mixturewas formed in an amount of about 4% by weight of the total mixture.

The resulting micro-particulate medium was subjected to tabletting undercompaction pressure of about 6 SCU. The resulting tablets had excellentappearance, a good surface and high structurally integrity. Furthermore,the tablets disintegrated immediately in the mouth of the consumer. Thecalcium release characteristics have been set forth below in the CalciumRelease Table.

Antacid Example IX

Another antacid example was prepared using the formulation set forthbelow.

                  TABLE IX    ______________________________________    ANTACID    Ingredient              Percentage    ______________________________________    Antacid Agent    CaCO.sub.3                  29.50%    Mg (OH).sub.2                5.79%    M2                          60.12%    Peppermint Flavor       0.12%    (Peppermint Oil)    Vegetable Oil           0.50%    Flow Agent    Syloid 244                  1.00%    Cab-O-Sil   0.40%    Starch                  2.00%    High Intensity Sweetener                            0.07%    (Aspartame)    Lubricant (Mg Stearate) 0.50%                            100.00%    ______________________________________

The ingredients were mixed and subjected to agglomeration to form aflowable, compactible micro-particulate medium in the presence of 200proof ethanol. The ethanol was added and mixed with the ingredients toform the agglomeration.

The resulting agglomerate was subjected to a tabletting force of about 6SCU. The resulting tablets had excellent appearance and a highstructural integrity and good surface qualities. The tabletsdisintegrated immediately in the mouth of the consumer. Furthermore, thetablets were subjected to calcium release and were shown to haveexcellent calcium release characteristics. The results are set forth inthe Calcium Release Table below.

Antacid Example X

Another antacid example was prepared using the formulation set forthbelow.

                  TABLE X    ______________________________________    ANTACID    Ingredient                 Percentage    ______________________________________    Antacid Agent    CaCO.sub.3                     29.50%    Mg (OH).sub.2               5.79%    M1                             59.89%    Flavoring                      0.35%    Vegetable Oil                  0.50%    Flow Agent    Syloid 244 1.00%    Cab-O-Sil  0.40%    Starch                     2.00%    High Intensity Sweetener (Aspartame)                               0.07%    Lubricant (Mg Stearate)    0.50%    Red Coloring (FD&C No. 40) 0.04%                               100.00%    ______________________________________

The above ingredients were thoroughly mixed and then agglomerated by useof 200 proof ethanol in an amount of about 4% by weight of the totalmixture. The resulting micro-particulate medium was subjected to tabletformation under a compaction force of about 6 SCU.

The resulting tablets had a uniform red surface appearance and goodstructural integrity. Furthermore, the tablets disintegrated immediatelyin the mouth of the consumer. The tablets were then subjected to calciumrelease tests and the results have been reported herein in the CalciumRelease Table.

Calcium Release Characteristics

An assay was conducted in order to determine the calcium releasecharacteristics of the samples prepared as set forth above. The calciumrelease characteristics were prepared in accordance with the protocolset forth in the United States Pharmacopeia.

Several tablets were weighed and powdered, and the weight of each of thesamples tested had a dosage amount of 550 mg. This powder was introducedto water to which 10 mm. of 1 N HCl had been added. This was boiled for30 minutes, allowed to cool, and then transferred to a 100 mL volumetricflask with the aid of water. This was diluted with water to volume,mixed, and filtered. Twenty (20) mL. of the filtrate was transferred toa suitable container and diluted with water to 100 mL. Fifteen (15) mL.of 1 N NaOH was added along with 5 mL. of triethanolamine, and 100 mg.of hydroxy naphthol blue trituration, and titrated with 0.05 M ofdisodium ethylenediamine-tetraacetate VS until the solution is a deepblue color. Each mL. of 0.05 disodium ethylenediamine-tetraacetate isequivalent to 5.004 mg. of calcium carbonate (CaCO₃). The results of theassay have been set forth below in the Calcium Release Table.

                  TABLE    ______________________________________    CALCIUM RELEASE    Sample      % Calcium Release    ______________________________________    I.          95.76    IIa.        95.21    IIb.        95.76    III.        95.48    IV.         94.93    Va.         96.03    Vb.         93.58    Vc.         96.03    VI.         94.47    VIII.       98.64    IX.         95.25    X.          94.92    ______________________________________

As can be seen, the calcium released at 30 minutes was excellent on allthe samples prepared in accordance with the present invention.

Antacid Example XI

Chewable, fast dissolving tablets containing calcium carbonate were madeas follows. The floss referred to in section I was used in both tablets.

The following example illustrates the preparation of chewable antacidtablets.

    ______________________________________    I.      Floss (Matrix) Formulation    ______________________________________    Sucrose                  58.5%    Mannitol                 23%    Sorbitol                 15%    Polydextrose             3%    Tween 80                 0.5%    ______________________________________

The sucrose and Tween 80 were blended in a AFM or Hobart 160 quartplanetary mixer at 70 to 120 rpm for 5 to 10 minutes. The mannitol,sorbitol, and polydextrose were added and blended for additional 15 to20 minutes. The blend was then subjected to shearform process at 60 Hzand 180-185° C. temperature using the 5" crown head described in U.S.Ser. No. 08/854,344, filed May 12, 1997. The floss manufactured waschopped by the turning blades rotating at 60 Hz and collected by thecyclone. The chopped floss was treated with ethanol (200 Proof, 4% byweight of the formulation) by spraying the ethanol on the floss in aplanetary mixer and mixing it for 10 minutes. The floss was placed inGruenberg Oven trays and dried at 35-40° C. for 60 minutes in the oven.The floss was then milled/sieved through a 20 mesh screen using a QuadroComil.

    ______________________________________    II.     Tablet Formulations    ______________________________________    A.        Cherry Flavor            Calcium Carbonate USP                            36.07%            Floss           55.51%            Mannitol USP     5.00%            Artificial Cherry Flavor                             0.10%            Cherry Cream     0.25%            Aspartame        0.07%            Syloid 244FP     1.25%            Cab-O-Sil        0.50%            D&C Red #27 Aluminum Lake                             0.25%            Magnesium Stearate                             1.00%    ______________________________________

The calcium carbonate was blended and sieved in a AFM or Hobart 106quart planetary mixer at 70 to 120 rpm for 5 to 10 minutes. The flavors,mannitol, color, and sweeteners were blended for 5 minutes in a separatecontainer and added to the planetary mixer. The flow agents were addedand blended for additional 10 minutes. The magnesium stearate was addedand blended for additional 5 minutes. The blend was compressed on arotary tablet press at 5 SCU hardness, 0.276 inch thickness, 1.525 gtablet weight, 5/8 inch dimple face round tooling. Using the sameprocedure used for the cherry flavor, tablets containing peppermintflavors were prepared from the following formulation.

    ______________________________________    B.        Peppermint Flavor    ______________________________________            Calcium Carbonate USP                             36.07%            Floss            55.65%            Mannitol USP     5.00%            Betanat Natural Peppermint Flavor                             0.15%            Peppermint Oil of Kennewick                             0.05%            Natural Whipped Cream                             0.20%            Magnasweet 100   0.03%            Asparatme        0.10%            Syloid 244FP     1.25%            Cab-O-Sil        0.50%            Magnesium Stearate                             1.00%    ______________________________________

The peppermint tablets were pressed to 5 SCU hardness, 0.276 inchthickness, and 1.525 g tablet weight using 5/8 inch dimple face roundtooling.

While there had been described what are presently believed to be thepreferred embodiments of the present invention, those skilled in the artwill appreciate that other and further embodiments can be made withoutdeparting from the spirit of the invention and it is intended to includeall such further modifications and changes as come within the true scopeof the claims as set forth herein.

What is claimed is:
 1. A method of preparing quick dissolve comestibleunits comprising:a) initiating crystallization of shearform matrix; b)before or after initiating crystallization combining acrystallization/binding promoter and an additive with said shearformmatrix to form flowable, compactible micro-particulates; and c)compacting the combination resulting from step "b", which includes atleast partially crystallized shearform matrix, to form said comestibleunits.
 2. A method of preparing a chewable quick dissolve comestibleunit comprising:a) initiating crystallization of shearform matrixparticles by contacting them with a crystallization/binding promoter; b)after initiating crystallization, combining at least one additive withthe particles; and c) compressing the product of step b) to form saidcomestible unit.
 3. The method of claim 2 wherein the additive comprisesat least one active ingredient.
 4. The method of claim 3 wherein theactive ingredient is calcium carbonate.
 5. The method of claim 4 whereinthe shearform matrix is a floss prepared from a composition containing:58.5% sucrose, 23% mannitol, 15% sorbitol, 3% polydextrose, and 0.5%Tween
 80. 6. The method of 5 wherein the comestible unit is preparedfrom a formulation containing an antacid and an H₂ -antagonist.
 7. Themethod of claim 6 wherein the formulation contains calcium carbonate. 8.A composition for preparing a chewable quick dissolve comestible unitcomprising:a) about 55 to 56% of a floss prepared from a compositioncontaining: 58.5% sucrose, 23% mannitol, 15% sorbitol, 3% polydextrose,and 0.5% Tween 80; and b) one or more active ingredients, wherein thefloss has been contacted with a crystallization/binding promoter.
 9. Thecomposition of claim 8 wherein the active ingredients include anantacid.
 10. The composition of claim 9 wherein the active ingredientsinclude calcium carbonate.
 11. The composition of claim 8 containing anantacid and an H₂ -antagonist.
 12. A comestible unit made from thecomposition of claim
 8. 13. A comestible unit made via the method ofclaim
 2. 14. The method of claim 1 wherein the crystallization/bindingpromoter is at least one selected from the group consisting of: ethanoland polyvinylpyrrolidone.
 15. The method of claim 2 wherein thecrystallization/binding promoter is at least one selected from the groupconsisting of: ethanol and polyvinylpyrrolidone.
 16. The composition ofclaim 8 wherein the crystallization/binding promoter is at least oneselected from the group consisting of: ethanol and polyvinylpyrrolidone.